The vitamin A metabolite, retinoic acid, has long been recognized to induce a broad spectrum of biological effects. In addition, a variety of structural analogues of retinoic acid have been synthesized that also have been found to be bioactive. Some, such as Retin-A.RTM. and Accutane.RTM., have found utility as therapeutic agents for the treatment of various pathological conditions. In addition, synthetic retinoids have been found to mimic many of the pharmacological actions of retinoic acid.
Medical professionals have become very interested in the therapeutic applications of retinoids. Among their uses approved by the FDA is the treatment of severe forms of acne and psoriasis. A large body of evidence also exists that these compounds can be used to arrest and, to an extent, reverse the effects of skin damage arising from prolonged exposure to the sun. Other evidence exists that these compounds may be useful in the treatment and prevention of a variety of cancerous and pre-cancerous conditions, such as melanoma, cervical cancer, some forms of leukemia, oral leukoplakia and basal and squamous cell carcinomas. Retinoids have also shown an ability to be efficacious in treating and preventing diseases of the eye, cardiovascular system, immune system, skin, respiratory and digestive tracts, and as agents to facilitate wound healing and modulate programmed cell death (apoptosis).
Major insight into the molecular mechanism of retinoic acid signal transduction was gained in 1988, when a member of the steroid/thyroid hormone intracellular receptor superfamily was shown to transduce a retinoic acid signal. Evans, Science, 240:889-95 (1988); Giguere et al., Nature, 330:624-29 (1987); Petkovich et al., Nature, 330: 444-50 (1987). It is now known that retinoids regulate the activity of two distinct intracellular receptor subfamilies; the Retinoic Acid Receptors (RARs) and the Retinoid X Receptors (RXRs), including their isoforms, RAR.alpha., .beta., .gamma. and RXR.alpha., .beta.,.gamma.. In this regard, an endogenous low-molecular-weight ligand which modulates the transcriptional activity of the RARs is all-trans-retinoic acid (ATRA), while an endogenous ligand for the RXRs is 9-cis retinoic acid (9-cis). Heyman et al., Cell, 68:397-406 (1992) and Levin et al. Nature, 355:359-61 (1992).
Although both the RARs and RXRs respond to ATRA in vivo, due to the in vivo conversion of some of the ATRA to 9-cis, the receptors differ in several important aspects. First, the RARs and RXRs are significantly divergent in primary structure (e.g., the ligand binding domains of RAR.alpha. and RXR.alpha. have only 27% amino acid identity). These structural differences are reflected in the different relative degrees of responsiveness of RARs and RXRs to various vitamin A metabolites and synthetic retinoids. In addition, distinctly different patterns of tissue distribution are seen for RARs and RXRs. For example, in contrast to the RARs, which are not expressed at high levels in the visceral tissues, RXR.alpha. mRNA has been shown to be most abundant in the liver, kidney, lung, muscle and intestine. Finally, the RARs and RXRs have different target gene specificity. For example, response elements have recently been identified in the cellular retinal binding protein type II (CRBPII) and Apolipoprotein AI genes which confer responsiveness to RXR, but not RAR. Furthermore, RAR has also been recently shown to repress RXR-mediated activation through the CRBPII RXR response element (Manglesdorf et al., Cell, 66:555-61 (1991)). These data indicate that two retinoic acid responsive pathways are not simply redundant, but instead manifest a complex interplay.
In view of the related, but clearly distinct, nature of these receptors, retinoids which are more selective for the RAR subfamily than the RXR subfamily provide the capacity for independent control of the physiologic processes mediated by the RARs versus RXRs. While offering the distinct therapeutic advantages noted above, RAR agonists also manifest an array of undesired side effects, depending upon the therapeutic dose level employed, including, but not limited to, headache, teratogenesis, mucocutaneous toxicity, musculoskeletal toxicity, dyslipidemias, skin irritation and hepatotoxicity, as well as the relatively rare, but serious, medical condition, hypervitaminosis A syndrome, which typically results from excessive intake of vitamin supplements. These side effects and conditions place limits on the application of RAR agonists in the treatment of various disease states.
Structurally distinct RAR antagonists have been previously described. See, e.g., PCT Application WO 94/14777; Yoshimura et al., 38 J. Med. Chem., 3163 (1995); Kaneko et al., 1 Med. Chem. Res., 220 (1991); Apfel et al., 89 Proc. Natl. Acad. Sci., 7129; Eckhardt et al., 70 Toxicology Letters, 299 (1994); Keidel et al., 14 Molecular and Cellular Biology, 287 (1994); and Eyrolles et al., 37 J. Med. Chem., 1508 (1994). In addition, various polyene compounds have been disclosed to be useful in the treatment of inflammatory conditions, psoriasis, allergic reactions, and for use in sunscreens in cosmetic preparations. See eg., U.S. Pat. Nos. 4,534,979 and 5,320,833. Trienediolates of hexadienoic acids have also proved useful in the synthesis of retinoic and nor-retinoic acids. See M. J. Aurell, et al., 49 Tetrahedron, 6089 (1993). Further, trienoic retinoids have been shown to display both RAR and RXR agonist activity. See, PCT Patent Application WO 96/20913, published Jul. 11, 1996. However, no retinoid antagonist activity has been ascribed to these trienoic compounds.